COVID‐19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS‐CoV‐2 infection

Abstract

Background Pregnant women have been identified as a potentially at‐risk group concerning COVID‐19 infection, but little is known regarding the susceptibility of the fetus to infection. Co‐expression of ACE2 and TMPRSS2 has been identified as a prerequisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. Methods We performed a retrospective analysis of a single cell data repository. The data were then validated at both gene and protein level by performing RT‐qPCR and two‐colour immunohistochemistry on a library of second‐trimester human fetal tissues. Findings TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels only in the fetal intestine and kidney, and is not expressed in the fetal lung. The placenta also does not co‐express the two proteins across the second trimester or at term. Interpretation This dataset indicates that the lungs are unlikely to be a viable route of SARS‐CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the gastrointestinal tract is likely to be susceptible to infection due to its high co‐expression of both proteins, as well as its exposure to potentially infected amniotic fluid. Tweetable abstract This work provides detailed mechanistic insight into the relative protection & vulnerabilities of the fetus & placenta to SARS‐CoV‐2 infection by scRNAseq & protein expression analysis for ACE2 & TMPRSS2. The findings help to explain the low rate of vertical transmission.

SARS‑CoV‑2 infection and children: Insights from the 6th Workshop on Paediatric Virology (Review)

“…However, there is no increased risk for neonates apart from abnormal ophthalmologic outcomes identified in 15% of cases in a previous study (92). The absence of the co-expression of TMPRSS2 and ACE-2 in the placenta across the second trimester and at term, as well as the absence of ACE2 in the foetal lung help explain the rarity of vertical transmission (93). Fortunately, COVID-19 symptoms in children tend to be milder and slightly different from those in adults (89).…”

“…Looking back, 14 months after the '6th Workshop on Paediatric Virology', the volume of literature and data on SARS-CoV-2 and COVID-19 being published daily by the world scientific community is impressive (83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Since the workshop, as expected for a RNA virus, multiple variants of SARS-CoV-2 have emerged.…”

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…156 While most studies of COVID-19 in pregnancy focus on severe cases, there is growing evidence suggesting that both mild and severe SARS-CoV-2 infection during pregnancy alters inflammatory responses at the maternal-fetal interface despite the absence of ACE2 and TMPRSS2 expression. 155,159 Single-cell RNA sequencing of placental tissues from pregnant women with severe SARS-CoV-2 infection revealed that most of the DEGs between infected cases and controls belonged to maternal T cells and macrophages with minimal alterations in fetal cells. 157…”

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

“…The possibilities that a time window exists during pregnancy during which ACE2 and TMPRSS2 are coexpressed and that individual variability may influence the strength of this coexpression cannot be excluded. One possible reason for discordant results within the published literature may be the widespread presence of Fc receptors in the human placenta, as these are known to bind antibodies to varying affinities and may therefore lead to nonspecific staining [ 206 , 207 ].…”